More than 500,000 arthroplastic procedures and total joint replacements are performed each year in the United States. Approximately the same number of similar procedures are performed in Europe. Included in this number in Europe are about 90,000 total knee replacements and around 50,000 procedures to repair defects in the knee. These numbers are essentially the same in the U.S. (Praemer A., Furner S., Rice, D. P., Musculoskeletal conditions in the United States, American Academy of Orthopaedic Surgeons, Park Ridge, Ill., 1992, 125).
A method for regeneration-treatment of cartilage would be most useful and could be performed at an earlier stage of joint damage, thus reducing the number of patients needing artificial joint replacement surgery. With such preventive methods of treatment, the number of patients developing osteoarthritis would also decrease.
Techniques used for resurfacing the cartilage structure in joints have mainly attempted to induce the repair of cartilage using subchondral drilling, abrasion and other methods whereby there is excision of diseased cartilage and subchondral bone, leaving vascularized cancerous bone exposed (Insall, J., Clin, Orthop. 1974, 101, 61; Ficat R. P. et al., Clin. Orthop. 1979, 144, 74; Johnson L. L., in Operative Arthroscopy, McGinty J. B., Ed., Raven Press, New York, 1991, 341).
Coon and Cahn (Science 1966, 153, 1116) described a technique for the cultivation of cartilage synthesizing cells from chick embryo somites. Later, Cahn and Lasher (PNAS USA 1967, 58, 1131) used the system for analysis of the involvement of DNA synthesis as a prerequisite for cartilage differentiation. Chondrocyte cells respond to both EFG and FGF by growth (Gospodarowicz and Mescher, J. Cell Physiology) 1977, 93, 117), but ultimately lose their differentiated function (Benya et al., Cell 1978, 15, 1313). Methods for growing chondrocyte cells were described and are principally being used with minor adjustments by Brittberg, M. et al. (new Engl. J. Med. 1994, 331, 889). Cells grown using these methods were used as autologous transplants into knee joints of patients. Additionally, Kolettas et al. (J. Cell Science 1995, 108, 1991) examined the expression of cartilage-specific molecules such as collagens and proteoglycans under prolonged cell culturing. They found that despite morphological changes during culturing in monolayer cultures (Aulthouse, A. et al., In vitro Cell Dev. Biol., 1989, 25, 659; Archer, C. et al., J. Cell Sci. 1990, 97, 361; Hänselmann, H. et al., J. Cell Sci. 1994, 107, 17; Bonaventure, J. et al., Exp. Cell Res. 1994, 212, 97), when compared to suspension cultures grown over agarose gels, alginate beads or as spinner cultures (retaining a round cell morphology) tested by various scientists did not change the chondrocyte—expressed markers such as types II and IX collagens and the large aggregating proteoglycans, aggrecan, versican and link protein did not change (Kolettas, E. et al., J. Cell Science 1995, 108, 1991).
Wakitani et al. (Tissue Engineering 4 (4),429 (1989) described the use of collagen Type I gels in animal experiments to repair cartilage defects. In all instances, the major problem was the lack of biomechanical properties required for functional tissue repair.
The articular chondrocytes are specialized mesenchymal derived cells found exclusively in cartilage. Cartilage is an avascular tissue whose physical properties depend on the extracellular matrix produced by the chondrocytes. During endochondral ossification, chondrocytes undergo a maturation leading to cellular hypertrophy, characterized by the onset of expression of type X collagen (Upholt, W. B. and Olsen, R. R., In: Cartilage Molecular Aspects (Hall, B. & Newman, S., Eds.) CRC Boca Raton 1991, 43; Reichenberger, E. et al., Dev. Biol. 1991, 148, 562; Kirsch, T. et al., Differentiation, 1992, 52, 89; Stephens, M. et al., J. Cell Sci. 1993, 103, 1111).
Excessive degradation of type II collagen in the outer layers of articular surfaces of joints is also caused by osteoarthritis. The collagen network is accordingly weakened and subsequently develops fibrillation whereby matrix substances such as proteoglycans are lost and eventually displaced entirely. Such fibrillation of weakened osteoarthritis cartilage can reach down to the calcified cartilage and into the subchondral bone (Kempson, G. E. et al., Biochem. Biophys. Acta 1976, 428, 741; Roth, V. and Mow, V. C., J. Bone Joint Surgery, 1980, 62A, 1102; Woo, S. L.-Y. et al., in Handbook of Bioengineering (R. Skalak and S. Chien Eds), McGraw-Hill, New York, 1987, pp. 4.1-4.44).
Descriptions of the basic development, histological and microscopic anatomy of bone, cartilage and other such connective tissues can be found for example in Wheater, Burkitt and Daniels, Functional Histology, 2nd Edition (Churchill Livingstone, London 1987, Chp. 4). Descriptions of the basic histological anatomy of defects in bone, cartilage and other connective tissue also can be found for example in Wheater, Burkitt, Stevens and Lowe, Basic Histopathology, (Churchill Livingstone, London, 1985, Chp. 21).
Although the need for chondrocyte cell transplantation has been described at length at least in the above mentioned references, there remains a need for a satisfactory and effective procedure for cartilage repair either by transplantation or otherwise.